European Journal of Endocrinology (2009) 161 513–527 ISSN 0804-4643

REVIEW

Recommended evaluation of adrenal incidentalomas is costly,has high false-positive rates and confers a risk of fatal cancerthat is similar to the risk of the adrenal lesion becomingmalignant; time for a rethink?T J Cawood, P J Hunt, D O’Shea1, D Cole and S SouleDepartment of Endocrinology, Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand and 1Department of Endocrinology, St Vincent’sUniversity Hospital, Dublin, Ireland

(Correspondence should be addressed to T J Cawood; Email: tom.cawood@cdhb.govt.nz)

q 2009 European Society of E

Abstract

Objective: To assess the performance of current clinical recommendations for the evaluation of anadrenal incidentaloma.Design and methods: Literature review. Electronic databases (Pubmed, Ovid and citation searches fromkey articles) from 1980 to 2008 were searched. Eligible studies were those deemed most applicable tothe clinical scenario of a patient referred to an endocrinologist for assessment of an incidentallydetected adrenal mass. Surgical series, histopathological series and oncological series were reviewedand most were excluded.Results: The prevalence of functional and malignant lesions presenting as adrenal incidentaloma wassimilar to that quoted in most reviews, other than a lower incidence of adrenal carcinoma (1.9 vs4.7%) and metastases (0.7 vs 2.3%). The development of functionality or malignancy during follow-upwas rare (!1% becoming functional and 0.2% becoming malignant). During follow-up, false-positiverates of the recommended investigations are typically 50 times greater than true positive rates. Theaverage recommended computed tomography (CT) scan follow-up exposes each patient to 23 mSv ofionising radiation, equating to a 1 in 430 to 2170 chance of causing fatal cancer. This is similar to thechance of developing adrenal malignancy during 3-year follow-up of adrenal incidentaloma.Conclusion: Current recommendations for evaluation of adrenal incidentaloma are likely to result insignificant costs, both financial and emotional, due to high false-positive rates. The dose of radiationinvolved in currently recommended CT scan follow-up confers a risk of fatal cancer that is similar to therisk of the adrenal becoming malignant. This argues for a review of current guidelines.

European Journal of Endocrinology 161 513–527

Introduction

The scenario of a patient being referred to anendocrinologist for assessment of an adrenal incidenta-loma is becoming increasingly common, with improve-ments in imaging, increasing numbers of radiologicalinvestigations and an aging western world population.Current clinical management of such patients variesacross different centres and countries, as there is arelative lack of prospective outcome data on which tobase clinical recommendations, with practice generallyled by consensus (1) and expert opinion (2). Currentguidelines recommend various endocrine investigationsand radiological imaging at baseline. If the lesion isthought to be benign and non-functional, it is suggestedthat these tests are repeated at between 6 and 12monthly intervals for between 2 and 4 years, whichtypically would include between one and three follow-up computed tomography (CT) scans (1–3).

ndocrinology

While such an approach aims to avoid missing animportant functional or malignant lesion, because ofthe low prevalence of such conditions, investigationsneed to have very high sensitivity and specificity inorder to perform adequately in this environment. Theconsequence of low specificity is a high false-positiverate, which can result in significant financial andemotional cost, with the potential for further testsand/or unnecessary adrenalectomy. Furthermore, therehas been little attention paid to the possible harmfulconsequences of these investigations, in particular theexposure to ionising radiation from repeated CTscanning.

In order to assess the performance of the currentclinical recommendations, we first reviewed the litera-ture to find the most representative data on theprevalence of the various different pathologies that arelikely to present as an adrenal incidentaloma. Thisinvolved excluding those studies that may bias towards

DOI: 10.1530/EJE-09-0234

Online version via www.eje-online.org

514 T J Cawood and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161

malignant or functional lesions, such as surgical,histopathological and oncology series.

We then reviewed the performance of the variousinvestigations commonly used for assessment of adrenalincidentalomas, and applied the sensitivity and speci-ficity data to the likely prevalence of the differentpathologies at both initial presentation and duringfollow-up. Finally, we considered the potential inductionof fatal cancer as a result of exposure to ionisingradiation during repeated CT scanning.

Design and methods

A literature review was undertaken that was intendedto include studies that were most applicable to theclinical scenario of a patient referred to an endocrinol-ogist for assessment of an incidentally detected adrenalmass. Electronic databases (Pubmed and Ovid) from1980 to 2008 were searched, and additional citationsfrom key articles were also included. Pre-determinedexclusion criteria were surgical series, histopathologicalseries and oncological series, non-English studies(where inclusion criteria could not be accuratelydetermined), studies where a proportion of the patientsfrom larger multicentre studies may have been reportedelsewhere, studies where the study population was notO20 and studies where the study population wasneither a random sample nor a consecutive series.

Using the search terms ‘adrenal’ C ‘incidentaloma’and ‘adrenal’ C ‘incidental’, from 1980 to 2008, 828studies were found. After selecting those articlespertaining to the presentation or follow-up of adrenalincidentaloma, and only those written in English andwhere nO20, there were 68 articles remaining. Tothese articles were added a further 42 studies that wereobtained from citation searches from two leadingreviews (4, 5), giving a total of 110 articles. A numberof these were then excluded for a variety of reasonsincluding review articles (28), surgical series (21),studies where a proportion of the patients from largermulticentre studies may have been reported elsewhere(15) and studies including oncology patients (7) (Fig. 1).A small number of additional exclusion criteria wereapplied where methodological issues were such thatthese studies were not deemed most applicable to theclinical scenario of adrenal incidentaloma. Examples ofsuch exclusions are given below.

Prevalence of malignant and functionallesions in adrenal incidentaloma

The prevalence of malignant and functional lesions intrue adrenal incidentaloma is likely to have beenoverestimated in the literature for a variety of reasons.The consensus definition of a true adrenal incidenta-loma is an adrenal mass (O1 cm diameter) detected

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incidentally during imaging performed for extra-adrenal complaints (therefore excluding those withsevere or paroxysmal hypertension, hypokalaemia,clinical signs of hypercortisolism or hyperandrogenism).Also, those patients with a history of previous orcurrent malignancy, who represent a group of patientswith an increased risk of harbouring an adrenalmetastasis, should arguably be referred to an oncologyservice and excluded from consideration of trueincidentalomas. The operating characteristics of inves-tigation algorithms intended to reasonably exclude afunctional or malignant lesion in those with a low pre-test probability of malignancy may not be adequate inthis patient group.

A number of studies should be excluded fromconsideration if the aim is to determine the likelyprevalence of malignant and functional lesions in thosepresenting to endocrinologists as a true incidentaloma.Such studies include reports where some or all of thepatients are from surgical series (6–12). These lesionshave been deemed worthy of consideration for surgicalremoval, usually due to being larger or more suspiciousof malignancy. These data are likely to overestimate theprevalence of malignancy compared with those referredto endocrinology with true adrenal incidentaloma (13).Also, a number of papers have been misrepresentedin literature reviews (4), where the percentage ofmalignant lesions is reported as a percentage of thoseoperated on, rather than as a percentage of thoseinitially assessed with an incidentaloma, again exagger-ating the prevalence of malignant lesions (e.g. 13% ofthose operated on versus 6% of the total (14), 14%of those operated upon versus 3% of total (15) and 12%in those operated upon versus 2.6% of total (16)). Othersources of potential bias include studies involvingpatients with a history, current diagnosis or suspicionof malignancy (16–20), as well as studies where theadrenal lesion is not incidental, but was detected duringinvestigations based on symptoms, signs, hormonelevels and imaging studies (21). Additional problemsinclude studies where those with non-functionaladrenal masses are excluded (8), studies where theprimary imaging modality was ultrasound (and sosmaller lesions that are more likely to be benign may bemissed) (22) and studies that excluded patients withmasses smaller than 2 cm in diameter (23). Furtherproblems arise when including studies of selectedpatients rather than random or consecutive series(24), including studies of small size which areconsequently more influenced by random variation(e.g. where a single case can alter reported prevalenceby 5% (8, 17, 25)), and also studies where a proportionof the patients from larger multicentre studies may havepreviously been reported elsewhere in smaller reportsinvolving less centres, so potentially over-representingany random biases (26–34). More recent papers, not yetestablished in review literature, also have potentialsources of bias such as excluding lesions that appear

Figure 1 Inclusion and exclusioncriteria for selection of studies. Atpresentation, nine studies wereincluded (19, 30, 34, 36–42). Atfollow-up, 14 studies were included(19, 23, 33, 35, 36, 39, 41, 43–49).Four papers were included despitevarious methodological issues (19,23, 35, 47). These included a studythat included oncology patients,where the oncology patients wereexcluded in the assessment ofpresentation prevalence, but wereincluded in assessment of follow-upand where one oncology patientdeveloped an adrenal meta-stases (19). This may have ledto an overestimate of the chanceof developing adrenal metastasesin adrenal incidentaloma follow-up.The other papers were used in theassessment of follow-up andincluded a study where only benign-appearing lesions or adenomas(23, 35) were followed, or whereonly lesions O2 cm were followed(47), with these issues likely to havea negative (23, 35) and a positive(47) influence on the chance ofdeveloping functional or malignantlesions respectively. The authorsconsidered that with the relative lackof follow-up studies, even with thesemethodological issues, thesearticles had sufficient merit to justifytheir inclusion.

Evaluation of adrenal incidentalomas 515EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161

benign (Hounsfield units (HU)!10) or patients with aspecific CT diagnosis such as haematoma and myeloli-poma (35).

In short, the most relevant studies for the scenario oftrue adrenal incidentaloma report on consecutive orunselected patients and exclude patients with a historyof previous or current malignancy. In addition, where alarger multicentre report includes patients that mayalready have been described in smaller single-centrestudies, only the larger report should be considered.Using these criteria and others detailed above, weconsider the studies in Table 1 to be the most relevant(30, 34, 36–42), plus one study where we haveexcluded the oncology patients (19).

From these studies, the expected prevalence ofprimary adrenal cancer in true adrenal incidentaloma

is less than half that quoted in recent extensiveliterature reviews (2, 4, 5) (mean 1.9%, median 1.4%,compared to mean 4.4–4.7%, (Table 2)). Similarly,when compared with earlier inclusive reviews, theseselected studies find the prevalence of metastasis is lessthan half (mean 0.7%, median 0.2%, compared to mean2.3%), the prevalence of phaeochromocytoma is twothirds (mean 3.1% compared to 5.2%), the prevalenceof aldosteronoma is half (mean 0.6% compared to1.1%), while the prevalence of subclinical Cushing’ssyndrome is similar (mean 6.4%, median 6.0%,compared to mean 6.6%).

Therefore, by including surgical series and theother above-listed biases, the current literature leadsto a significant overestimate of the chance of a trueadrenal incidentaloma being either malignant or

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Tab

le1

The

pre

vale

nce

of

likely

path

olo

gic

alentitie

sin

those

patients

pre

senting

with

true

adre

nalin

cid

enta

lom

a.

Ag

eS

ize

of

mass

Malig

nan

tB

en

ign

Year

Co

un

try

His

tory

of

mali

gn

an

cy

exclu

ded

Nu

mb

er

of

pati

en

tsM

ean

(years

)

Mean

or

media

n(c

m)

Prim

ary

adre

nal

carc

inom

a(%

)M

eta

stases

(%)

Tota

l(%

)

Non-

functional

(%)

Subcl

inic

al

Cushin

g’s

(%)

Phaeo

(%)

Ald

oste

r-onom

a(%

)

Herr

era

(34)

1991

US

AY

es

342

61

NG

1.2

0.3

98.6

95.9

1.2

2.9

0.0

Rein

cke

(40)

1992

Germ

any

Yes

66

58

3.1

0.0

0.0

100.0

85.3

11.8

1.5

1.5

Bard

et

(42)

1996

Fra

nce

Yes

46

NG

NG

4.3

2.2

93.5

NG

6.5

4.3

0.0

Seppel(3

8)

1996

Germ

any

Yes

85

54

3.6

2.0

NG

NG

NG

6.0

1.0

NG

Bondanelli

(37)

1997

Italy

Part

ially

a38

58

2.6

2.6

0.0

97.4

86.8

7.9

5.3

0.0

Basto

unis

(41)

1997

Gre

ece

NG

86

61

4.1

1.2

2.3

96.5

92.5

4.5

3.0

0.0

Mante

ro(3

0)

2000

Italy

Yes

b1004

56

3.6

4.7

0.7

94.6

85.1

9.2

4.2

1.6

Em

ral(3

9)

2003

Turk

ey

Yes

70

54

2.9

1.4

0.0

98.6

94.3

5.7

0.0

0.0

Tsveto

v(1

9)

2007

Isra

el

Yes

c67

59

2.5

0.0

0.0

100.0

88.1

4.5

5.3

1.8

Mean

200

58

3.2

1.9

0.7

97.4

89.7

6.4

3.1

0.6

95%

CI

0.8

–3.0

0.0

–1.4

95.7

–99.0

86.4

–93.0

4.4

–8.3

1.8

–4.3

0.0

–1.2

Media

n70

58

3.1

1.4

0.2

98.0

88.1

6.0

3.0

0.0

NG

,not

giv

en;

CI,

confidence

inte

rval.

aP

art

ially

(those

bein

gsta

ged

for

malig

nancy

were

exclu

ded).

bY

es,

iflu

ng,

kid

ney,

bre

ast

or

mela

nom

a.

cD

ata

from

the

67

with

no

know

nhis

tory

of

malig

nancy.

516 T J Cawood and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161

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functional, with the exception of subclinical Cushing’ssyndrome. With this lower pre-test probability ofdisease, the investigation algorithms based on thehigher prevalence rates may be suboptimal for mana-ging true adrenal incidentaloma. Furthermore, as CTtechnology has improved in the last two decades, theability to detect smaller lesions is improving, and sothe proportion of smaller, more likely benign lesionsthat are detected is likely to be increasing. Thisis supported by the negative correlation (RZK0.4,R2Z0.16) between the year of study and mean tumoursize in the studies listed in Table 1. Therefore, even thelower prevalence estimates derived from the studiesin Table 1 may be an overestimate when consideringthe population of patients now referred with adrenalincidentaloma, which may include an increasingproportion of patients with smaller adrenal masses.

There are no data giving an accurate figure for theprevalence of adenomas among adrenal incidentalo-mas. This is relevant because the performance of CTscanning in assessing adrenal lesions is partly relatedto its ability to identify lipid-rich lesions includingadenoma by incorporating HU into diagnostic algo-rithms. Adenomas may be non-functional, but alsoinclude lesions causing subclinical Cushing’s syndromeand hyperaldosteronism (HA). Adenomas may beunder-represented among surgical series as themajority of small, benign, non-functional lesions willbe adenomas and hence less likely to be surgicallyexcised. Estimates of the prevalence of adrenal adeno-mas among adrenal incidentalomas vary. One studysuggests a prevalence of 52% (4), although this reviewdoes include a number of surgical series. The realprevalence of adenomas is likely to be nearer 80%,this being the total of apparently non-functioningadenomas (71.2%), plus lesions causing subclinicalCushing’s syndrome (7.9%) and lesions causing HA(1.2%) (5).

Follow-up of adrenal incidentalomas

Studies addressing the follow-up of adrenal incidenta-loma are relatively low in number and have aconsiderable degree of heterogeneity. The inclusion ofadrenal incidentaloma studies where the adrenalect-omy rate is 100% would help to provide more accuratehistological data and reduce the chance of under-diagnosis, but such a study would be unethical, with thegeneral experience being that relatively few patientsdevelop malignancy or clinically apparent functionallesions. Mindful of these and other limitations, weconsider the studies included in Table 3 (19, 23, 33, 35,36, 39, 41, 43–49) to be those most relevant whenconsidering the natural history of adrenal incident-alomas that are initially considered benign andnon-functioning.

Tab

le2

The

pre

vale

nce

of

likely

path

olo

gic

alentitie

sin

those

patients

pre

senting

with

true

adre

nalin

cid

enta

lom

aas

report

ed

inth

ecurr

ent

paper,

com

pare

dto

recent

leadin

gre

vie

ws

(4,

5,

84).

Fir

st

au

tho

rY

ear

Nu

mb

er

of

stu

die

sP

ati

en

tsp

er

stu

dy

Mean

Pati

en

tsp

er

stu

dy

Media

nA

ge

(years

)M

ean

Siz

eo

fm

ass

(cm

)M

ean

Ad

ren

al

Ca

(%)

Meta

sta

ses

(%)

Su

bcli

nic

al

Cu

sh

ing

’s(%

)P

haeo

(%)

Ald

oste

ron

om

a(%

)

Mansm

ann

(4)

2004

33

114

38

57

3.4

4.7

NG

‘5–47’

5.0

‘1.6

–3.8

’B

arz

on

(5)

2003

26

148

64

57

3.5

4.4

2.1

7.9

5.6

1.2

Young

(84)

2007

13

154

59

57

3.6

4.7

2.5

5.3

5.1

1C

urr

ent

paper

2009

9200

70

58

3.2

1.9

(media

n1.4

)

0.7

(media

n0.2

)

6.4

(media

n6.0

)

3.1

0.6

Evaluation of adrenal incidentalomas 517EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161

For any test proposed for follow-up of adrenalincidentalomas, the following should be considered:i) what is the sensitivity and specificity of the test,particularly in the low-prevalence situation of adrenalincidentaloma follow-up, ii) what is the consequence offalse-negative and false-positive results, iii) are there anyrisks associated with the test and iv) what are thefinancial costs of the test?

Tests for subclinical Cushing’s syndrome

Subclinical Cushing’s syndrome has not been ade-quately defined, and the natural history of thissyndrome is unknown (4). The definitions of subclinicalCushing’s syndrome vary widely in the literature. Nocurrent test or definition accurately identifies those atrisk of complications (such as glucose intolerance,obesity, osteoporosis and adrenal failure followingadrenalectomy). Current definitions of subclinicalCushing’s syndrome include autonomous cortisolsecretion in patients who do not have the typical signsand symptoms of hypercortisolism (2). Others usedefinitions that stipulate the absence of clinical signsof cortisol excess plus at least two biochemicalabnormalities of the hypothalamic–pituitary–adrenal(HPA) axis (30, 50). The main drawback of thesedefinitions is that the more tests that are performedlooking for HPA abnormalities, the higher the rate ofdiagnosis of subclinical Cushing’s syndrome. Further-more, if the disease is defined by laboratory abnormal-ities, rather than by some clinical correlate, it becomesdifficult to define false positives, as all positives are bydefinition indicative of the diagnosis.

The absence of an agreed definition of subclinicalCushing’s syndrome or gold standard test for diagnosingsubclinical Cushing’s syndrome makes the determina-tion of specificity and sensitivity of tests used to diagnosesubclinical Cushing’s syndrome problematic. The NIHposition statement (2) and others including theEndocrine Society (51) recommend using the 1 mgdexamethasone (DXT) as the initial test for subclinicalCushing’s syndrome. Applying the commonly useddefinition of subclinical Cushing’s syndrome (theabsence of clinical signs of cortisol excess, plus two ormore abnormalities of basal or dynamic test of the HPAaxis), the largest study is from Mantero et al. (30)comprising 946 adrenal incidentalomas, and 854 werecharacterised as non-hypersecreting and 92 as sub-clinical Cushing’s syndrome. Tests used to evaluatethe HPA axis included urinary-free cortisol (UFC),plasma ACTH, serum DHEA sulphate (DHEAS), serum17-hydroxyprogesterone (17-OHP), 24-h cortisolrhythm, 1 mg DXT, 100 mg CRH test and 250 mg ACTHtest, although not all tests were performed on all patients.

The results (Table 4) indicate that w15% of lesionsclassified as non-hypersecreting demonstrate a singleabnormal test of the HPA axis, a significantly lower

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Table 3 Studies detailing the follow-up of adrenal incidentalomas thought to be benign and non-functioning after initial diagnostic work-up.

First author Year

Number

of

patients

(nO20)

Mean

age

(years)

Size of

masses

(mean or

median)

Follow-

up

duration

(years)

Increased

in size

(%)

Unchanged

in size

(%)

Decreased

in size

(%)

Became

malignant

(%)

Developed

adrenal

Ca (%)

Developed

metastases

(%)

Benign

(%)

Became

functional

(%)

Developed

Cushing’s

syndrome

(%)

Developed

subclinical

Cushing’s

syndrome

(%)

Developed

phaeochro-

mocytoma

(%)

Developed

aldoster-

onoma (%)

Song (35) 2007 71 NG NG 2.7 0.0 NG NG 0 0 0 100 NG NG NG NG NG

Song (35) 2007 209 NG NG NG NG NG NG 0 0 0 100 NG NG NG 1 NG

Song (35) 2007 41 NG NG 3.3 NG NG NG 0 0 0 100 NG NG NG NG NG

Favia (23) 2000 90 NG NG 1.8 NG NG NG 0 0 0 100 0 0 0 0 0

Barzon (43) 1999 75 56 2.5 4.0 16.0 81.0 2.7 0 0 0 100 8 2.7 4a 1.3 0

Bulow (44) 2006 229 64 2.5 2.1 7.4 87.4 5.2 0 0 0 100 2.6 1.3 0 0.7 0

Tsvetov (19) 2007 88 NG 2.6 2.0 12.5 87.5 0.0 1.1 0 1.1b 98.9 0 0 0 0 0

Barry (33) 1998 231 64 2.0 7.0 4.0 96.0 0.0 0 0 0 100 0 0 0 0 0

Libe (45) 2002 64 61 2.5 2.1 20.0 0.0 0.0 1.6c 0 0 98.4 0 0 0 0 0

Siren (46) 2000 27 59 2.5 7.1 25.0 31.0 44.0 0 0 0 100 0 0 0 0 0

Rossi (36) 2000 32 NG NG 2.8 15.6 84.6 0.0 0 0 0 100 0 0 0 0 0

Bastounis (41) 1997 60 NG 3.2 3.6 3.7 97.3 0.0 0 0 0 100 NG 0 NG NG NG

Grossrubatscher

(47)

2001 53 NG 2.5 2.0 41.5 47.2 11.3 0 0 0 100 0 0 0 0 0

Emral (39) 2003 60 NG NG 2.0 0.0 NG NG 0 0 0 100 0 0 0 0 0

Mantero (49) 2000 53 NG NG O1 26.4 NG NG 0 0 0 100 0 0 0 0 0

Bencsik (48) 1995 27 NG !3 1.8 3.7 NG NG 0 0 0 100 0 0 0 0 0

Mean 83.8 60.8 2.5 3.2 14.7 68.0 7.0 0.2 0.0 0.1 99.8 0.9 0.3 0.3 0.2 0.0

95% CI 8.0–21.3 45.8–90.2 K2.4–16.4 0.0–0.4 0.0–0.0 0.0–0.2 99.6–

100.0

K0.5–2.2 K0.1–0.7 K0.4–1.0 K0.1–0.4 0.0–0.0

Median 60.0 61.0 2.5 2.1 14.1 84.6 0.0 0.0 0.0 0.0 100.0 0.0 0.0 0.0 0.0 0.0

NG, not given; CI, confidence interval.aThese patients had any abnormal baseline hormonal test repeated, plus up to eight hormonal assessments in total, including 0800 h cortisol, 1800 h cortisol, morning ACTH, DHEAS, 17-OHP, 1 mg DXT and insome cases CRH test. The paper by Song is included three times, as these subgroups of patients were followed up either radiologically (71 patients), by histology or imaging (209 patients), or by clinicalinformation (41 patients).bRepresents one case of renal cell cancer metastasis in a patient with a known history of renal cell carcinoma; arguably this study should have been excluded from this analysis.cRepresents one case of adrenal non-Hodgkin’s lymphoma.

51

8TJCaw

oodandoth

ersE

UR

OP

EA

NJO

UR

NA

LO

FE

ND

OC

RIN

OL

OG

Y(2

00

9)161

ww

w.e

je-o

nlin

e.o

rg

Table 4 Hormonal evaluation of non-hypersecreting adrenalincidentalomas and lesions characterised as causing subclinicalCushing’s syndrome, from Mantero (30).

Test

Non-hypersecreting(%)

SubclinicalCushing’ssyndrome (%)

Low morning ACTH levels 15 79Above normal UFC 11 75Abnormal circadian rhythm

of plasma cortisol17 43

Blunted ACTH responseto CRH

17 55

Cortisol not adequatelysuppressed by 1 mgdexamethasone

10 73

Evaluation of adrenal incidentalomas 519EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161

proportion than those classified as subclinical Cushing’ssyndrome. However, in the light of the current definitionof subclinical Cushing’s syndrome (requiring two ormore abnormal tests of the HPA axis), it is relevant tonote that even the use of two out of the three mostfrequently abnormal HPA tests would still fail to capturea significant proportion of patients otherwise labelledas subclinical Cushing’s syndrome had more tests beenperformed. For example, an abnormal 1 mg DXT testplus a low ACTH only identified 55% of those in thesubclinical Cushing’s syndrome group, and an abnor-mal 1 mg DXT plus above-normal UFC only identified50% of the subclinical Cushing’s syndrome group.Therefore, a single 1 mg DXT will label 10% of the non-hypersecretors as subclinical Cushing’s syndrome (10%false positive, specificity 90%) and will fail to label 27%of the subclinical Cushing’s syndrome group (27% falsenegative, sensitivity 73%). The cut-off for morningcortisol used in this study was 5 mg/dl (138 nmol/l),and more stringent cut-offs would increase the false-positive rate.

This 73% sensitivity of the 1 mg DXT in subclinicalCushing’s syndrome is lower than that found in otherstudies (92% (45), 100% (40), 86% (52) and 83%(53)), although these other studies were much smaller(6–12 patients, compared with 92 (30)). When takentogether, the 1 mg DXT was abnormal in 76%(110/131) (50) of those diagnosed with subclinicalCushing’s syndrome. The 90% specificity is in agree-ment with other studies of subclinical Cushing’ssyndrome (91% (2, 54)).

Tests for phaeochromocytoma

Recommendations for clinical practice from the FirstInternational Symposium on Pheochromocytoma arethat measurement of plasma or urinary fractionatedmetanephrines should be the first-line test for diagnosis,and reference intervals should favour sensitivity overspecificity (55).

Available studies are confounded by heterogeneity,examining different patient populations, with differentpre-test probabilities, and using total or fractionatedmetanephrines, with different laboratory cut-offs.Despite these limitations, there is a reasonable degreeof consistency with urinary metanephrines havingmedian sensitivity of 95% (77% (56), 97.1% (57), 90%(58), 100% (59), 100% (60), 94.7% (61) and 95% (62))and specificity of 95% (93% (56), 91.1% (57), 98% (58),94% (59), 99.1% (60), 95.3% (61) and 98% (62)).Plasma metanephrines have slightly higher sensitivity of98% (97% (58), 99% (56), 98% (63), 100% (64) and96% (65)), but lower specificity of 89% (85% (58), 89%(56), 92% (63), 96.7% (64) and 80% (65)).

Tests for HA

The recommended initial screening test for HA inhypertensive patients with adrenal incidentalomas isthe ratio of ambulatory morning plasma aldosteroneconcentration to plasma renin activity (Aldos/PRA)(2, 4, 13). Normokalaemic HA occurs at a frequency of7–38%, hence screening for HA should not be limited tothose who are hypokalaemic (4). The ability of theAldos/PRA to detect primary HA in resistant hyperten-sion varies, depending on numerous factors includingpatient selection criteria, medication use and laboratorycut-offs. Typical expected performance of theAldos/PRA is in the region of sensitivity 90% (78%(66), 89% (67), 92% (68), 90% (69), 96% (70) and100% (71)) and specificity 90% (83% (66), 84% (71),85% (70), 91% (69), 96% (67) and 100% (68)). Thereare less data on the performance of Aldos/PRA in thesetting of adrenal incidentaloma, although studies thathave retrospectively applied certain cut-offs haveachieved sensitivity of 100% and specificity of 95, 96and 99% (72–74). However, these figures may signi-ficantly overestimate the true performance of theAldos/PRA ratio as in the quoted series the prevalenceof HA was remarkably high at 14% (73) and 12% (10 ofthe 50 incidentaloma patients) (74), when comparedwith the expected prevalence of 1% in all adrenalincidentaloma patients and 4% in hypertensive adrenalincidentaloma patients (72). Of note, the true sensitivityof the Aldos/PRA as a screening test in adrenalincidentaloma remains unclear, as without additionaldefinitive tests such as saline suppression in patientswith a normal Aldos/PRA ratio, the sensitivity of theratio for the detection of HA in the hypertensive patientwith an incidentaloma remains conjectural.

Taken together, the sensitivity and specificity of theAldos/PRA for detecting HA in patients with hyperten-sion and an adrenal incidentaloma are likely to be in theregion of 90–100%, depending on the cut-offs used andpatient group studied, with a figure of 95% beingarguably a reasonable estimate.

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Tab

le5

The

perf

orm

ance

of

recom

mended

tests

for

the

initia

levalu

ation

of

1000

adre

nalin

cid

enta

lom

as.

Of

1000

ad

ren

al

incid

en

talo

mas

Pre

vale

nce

(%)

Test

Sen

sit

ivit

y(%

)S

pecifi

cit

y(%

)T

est

po

sit

ive

Test

neg

ati

ve

Tru

ep

osit

ive

Tru

en

eg

ati

ve

Fals

en

eg

ati

ve

Fals

ep

osit

ive

Subclin

icalC

ushin

g’s

6.4

1m

gD

XT

73

90

141

859

47

842

17

94

a

Phaeo

3.1

Urinary

meta

nephrines

95

95

78

922

29

920

249

Phaeo

3.1

Pla

sm

am

eta

nephrines

98

89

137

863

30

862

1107

Ald

oste

ronom

a0.6

Renin

/ald

o95

95

56

944

5.7

944

0.3

50

Adenom

a80.0

CT

75

95

610

390

600

190

200

10

Adre

nalcancer

1.9

CT

75

67

338

662

14

657

5324

Pre

vale

nce

rate

sare

taken

from

Table

1,

with

the

pre

vale

nce

of

adenom

as

estim

ate

dfr

om

(5).

aN

ote

ism

ade

of

the

fact

that

the

fals

e-p

ositiv

era

teof

asin

gle

1m

gD

XT

inth

edia

gnosis

of

subclin

icalC

ushin

g’s

syndro

me

isderived

from

the

stu

dy

by

Mante

ro(3

0)

and

ishere

com

paring

the

dia

gnostic

perf

orm

ance

of

asin

gle

1m

gD

XT

again

st

avariety

of

two

or

more

tests

that

were

used

toassess

the

hypoth

ala

mic

–pituitary

–adre

nalaxis

.

520 T J Cawood and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161

Imaging as a test for malignancy

The ability of radiological imaging to detect malignantadrenal incidentalomas varies depending upon thecriteria used. CT is generally better able to differentiatebetween adenomas and non-adenomatous lesions,compared with its ability to diagnose or exclude specificpathological entities.

When selecting CT criteria that discriminate betweenadenomatous and other lesions, the majority of studieshave determined thresholds for parameters such as HUin a retrospective manner. These thresholds are likely toperform less well when tested prospectively. Only aminority of studies (75) have prospectively evaluatedthe performance of HU thresholds obtained from CTadrenals, and derived a sensitivity of 71% and specificityof 100% for diagnosing adrenal adenomas. Studies varyin their patient populations, inclusion and exclusioncriteria, threshold levels and/or combination ofthresholds (e.g. pre-contrast CTCdelayed contrastwash-out thresholds). There are also a variety ofmethods by which the malignant or benign status ofthe lesions has been determined, and many of thestudies are too small to have any identified adrenocor-tical carcinomas (76, 77), and hence the ability of thegiven thresholds to identify these lesions is unknown.

With these caveats in mind, the most studied imagingmodality for diagnosis of adrenal adenomas is CT, withor without delayed contrast washout. The typicalperformance of CT is sensitivity of 64% (78), 66.7% inlesions over 2 cm (79), 71% (75), 72% (76), 92% using10 min contrast washout (80), 96% (81) and 96%using 3 min contrast washout (82). Using combinedparameters, CT performance for identifying adenomascan range from 42% (using non-contrast CT HU%20plus size %4 cm (83)) to 100% (when lesions with pre-contrast HU!0 are excluded (considered benign) andthose with pre-contrast HUO43 are excluded(considered suspicious of malignancy) and when cysts,myelolipomas and phaeochromocytomas are excluded,and using an absolute percentage contrast washoutthreshold at 10 min of 52% (77)). Collating the datafrom these varied studies gives an approximatesensitivity of 75% (mean sensitivity 78% and mediansensitivity 72%). This 75% figure is consistent withother estimates (75% (79) and 68–89% (4)).

Typical specificity of CT for diagnosing adrenaladenomas is 85.7% (79) in lesions over 2 cm, 92%using delayed enhanced CT (82), 95% (78), 95% (76),95% using delayed enhanced CT (80), 96% usingdelayed CT (81), 100% (75), 98% using variousexclusions as detailed above (77) and 100% usingnon-contrast CT HU%20 plus size %4 cm (83).Collating the data from these varied studies gives anapproximate specificity of 95% (mean and medianspecificity of 95%). This 95% figure is consistent withother estimates (93–100% (4)).

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and

non-f

unctionin

g,

follo

wed

for

2years

.

Tru

en

eg

ati

ve

Fals

en

eg

ati

ve

Fals

ep

osit

ive

897

1100

a

948

050

888

0110

950

050

948

0.5

50

949

0.2

550

670

0330

ante

ro(3

0)

and

ishere

com

paring

the

dia

gnostic

Evaluation of adrenal incidentalomas 521EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161

Studies addressing the detection of adrenocorticalcarcinoma, which have found a 4 cm cut-off, had 90%sensitivity, even though 76% of lesions greater than4 cm were benign (27, 84). Another study found that intumours O3 cm, CT had a sensitivity of 75% andspecificity of 67% for detecting adrenocortical carci-noma (85). Hence, the ability of CT to correctly diagnosethis low-prevalence pathology is considerably lowercompared to the ability of CT to differentiate betweenadenomatous and other non-adenomatous lesions.

The performance of the recommended investigationsfor the initial evaluation and during the follow-up ofadrenal incidentalomas initially thought to be benignand non-functional is given in Tables 5 and 6.

Tab

le6

The

perf

orm

ance

of

recom

mended

tests

inth

efo

llow

-up

evalu

atio

nof

1000

adre

nalin

cid

enta

lom

as

initia

llyth

ought

tobe

benig

n

Of

1000

ad

ren

al

incid

en

talo

mas,

init

iall

yth

ou

gh

tto

be

ben

ign

an

dn

on

-fu

ncti

on

al,

foll

ow

ed

for

2years

Pre

vale

nce

(%)

Test

Sen

sit

ivit

y(%

)S

pecifi

cit

y(%

)T

est

po

sit

ive

Test

neg

ati

ve

Tru

ep

osit

ive

Subclin

icalC

ushin

g’s

0.3

1m

gD

XT

73

90

102

898

2P

haeo

0.2

Urinary

meta

nephrines

95

95

50

950

2P

haeo

0.2

Pla

sm

am

eta

nephrines

98

89

112

888

2A

ldoste

ronom

a0.0

Renin

/ald

o95

95

50

950

0M

alig

nancy

0.2

CT

75

95

51.5

948.5

1.5

Meta

stases

0.1

CT

75

95

50.8

949.3

0.8

Adre

nalcancer

0.0

CT

75

67

330

670

0

Pre

vale

nce

rate

sare

taken

from

Table

3,

usin

gth

em

ean

valu

e(m

edia

nvalu

es

are

all

zero

).aN

ote

ism

ade

of

the

fact

that

the

fals

e-p

ositiv

era

teof

asin

gle

1m

gD

XT

inth

edia

gnosis

of

subclin

icalC

ushin

g’s

syndro

me

isderived

from

the

stu

dy

by

Mperf

orm

ance

of

asin

gle

1m

gD

XT

again

st

avariety

of

two

or

more

tests

that

were

used

toassess

the

hypoth

ala

mic

–pituitary

–adre

nalaxis

.

Risk of cancer due to imaging-associatedradiation exposure

The most commonly used imaging modality inassessing adrenal incidentaloma is CT. X-ray imagingtechniques, including CT, involve ionising radiation,which carries an associated risk of inducing malig-nancy. The magnitude of that risk has been estimatedfrom studies where populations have been exposed to aknown dose of ionising radiation, and the subsequentincrease in cancer-associated deaths has been ascer-tained. This has been studied in depth by the UnitedNations Scientific Committee on the Effects of AtomicRadiation who publish regular reports, updated by thelatest mortality data. The latest report assessinglifetime mortality risk for total cancer associated withionising radiation was published in 2006 (86), andincludes data from a cohort of 86 611 survivors ofatomic bombings in Japan. Although some of thiscohort received large doses of radiation (up to4000 mSv), the cohort is fundamentally a moderatedose cohort, with the mean dose in the exposed groupbeing 200 mSv, with O50% of the exposed individualsin the cohort having doses !50 mSv (86, 87). Otherstudies have looked at fractionated or chronic low-doseexposure, including the IARC 15-country nuclearworker study (88), the Techa River contaminationwith liquid radioactive waste (89, 90) and the Semi-palatinsk study of the effects of local fallout from Sovietatmospheric nuclear weapons testing in Kazakhstan(91). There are concerns about bias in these fourstudies, which found substantially elevated risks forsolid cancers compared with the Japanese atomic bombcohort. These studies have low statistical precision,with wide confidence intervals for the risk estimates,which at least in the Techa River and nuclear workerstudy overlapped those from the Japanese cohort (86).

The effective dose of radiation associated with anabdominal CT scan is typically 10 mSv (92) (http://www.icrp.org/docs/Rad_for_GP_for_web.pdf; http://www.fda.gov/cdrh/ct/risks.html) (range 3.9 (93)–30 mSv (94)), which is equivalent to 3.3 years of

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522 T J Cawood and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161

natural background radiation exposure. The effectivedose of 10 mSv for CT abdomen compares to 2 mSv forCT head, 7 mSv for barium enema, 1.3 mSv for lumbarspine plain X-ray and 0.02 mSv for chest X-ray.Targeted CT of the adrenals may involve a lowerradiation dose, with a scan of the upper abdomendelivering w5 mSv (95). However, adrenal protocolsinvolving delayed contrast washout measurementrequire scanning the adrenal region twice, and hencethe total effective dose may be similar to a wholeabdomen scan, but is delivered to the upper abdominalorgans, which would consequently receive a higher dosethan during a whole abdominal scan.

There is direct epidemiological evidence from humanpopulations demonstrating that acute exposure toionising radiation at doses in the 10–50 mSv range(i.e. the organ dose range typically delivered by two orthree CT scans) increases the risk of some cancers (87).The corresponding CT-related risks can thus be directlyassessed without the need to extrapolate measured risksto lower doses (92). Risk estimates for radiation-inducedmortality for solid cancers and leukaemia, with a testdose of 10 mSv, are w4.8% per Sv. For a CT scan of theabdomen, the estimated associated lifetime absolute riskof cancer-related death as a direct consequence of theradiation dose received during the scan (10 mSv) is0.048% (86). An abdominal CT scan is thereforeestimated to cause one cancer-related death for every1000 (http://www.nap.edu/catalog/11340.html) –2000 (http://www.icrp.org/docs/Rad_for_GP_for_web.pdf) abdominal CT scans. More recent estimates basedon the lifetime risk of fatal cancer as a result of a singleabdominal CT scan in those aged over 30 years (as inthe vast majority of adrenal incidentaloma patients) arelower, in the region of one death per 5000 scans (92).The precise magnitude of the fatal cancer risk associatedwith CT scanning remains a matter of some debate, but

Table 7 Summary of current clinical recommendations (1–3).

Publication Hormonal tests Frequ

NIH Consensusstatement 2002 (1)

1 mg DXT, plasma-freemetanephrines, K andrenin/aldo in those withhypertension

Ann

Young, NEJM2007 (2)

1 mg DXT, urinary metanephrinesand catecholamines, K andrenin/aldo in those withhypertension

Ann

UpToDate, Feb2008 (3)

1 mg DXT, urinary metanephrinesand catecholamines, K andrenin/aldo in those withhypertension

Ann

Combinedstrategy

1 mg DXT, urinary (or plasma)metanephrines and catechol-amines, K and renin/aldo in thosewith hypertension

Ann

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it is generally accepted that although the risk isrelatively small, it is not zero, and hence should beconsidered before ordering CT imaging, especiallywhere the expected diagnostic yield is low.

Economic cost

In our institution, the cost of blood tests to assessfunctionality (routine biochemistry, cortisol as part of1 mg DXT, urinary catecholamines and metanephrines,renin and aldosterone) is wNZ$ 175 (US$ 120).Additional tests such as 24-h UFC, ACTH, DHEAS,17-OHP and serum catecholamines and metanephrinesadd an additional NZ$ 290 (US$ 200). An abdominalCT with contrast costs NZ$ 720 (US$ 500). Therefore,for baseline assessment, investigations cost betweenNZ$ 895 (US$ 620) and NZ$ 1185 (US$ 820),depending on how many blood and urine tests areordered.

Implications of current clinicalrecommendations

There are a number of consensus or clinical guidancepublications with arguably the more influentialpublications being those by Young (2), the UpToDatereview of which Young is the first author (3), and theNIH consensus statement (1). The recommendationsare summarised in Table 7. The routine application ofthe recommended strategy for follow-up of adrenalincidentalomas is likely to be costly in terms offinancial expense, radiation exposure and risk ofinducing fatal cancer. Furthermore, this approachcarries a high risk of false-positive diagnoses and theassociated emotional burden to each patient, while

encyDuration(years) Imaging Frequency

ual 4 Monitor those !4 cm,use additionalcriteria in those4–6 cm

Two CTs, at least 6months apart, nodata to supportcontinued imaging ifno increase in size

ual 4 Monitor those !4 cm CT at 6, 12 and 24months

ual 4 Monitor those !4 cm CT at 6, 12 and 24months

ual 4 Monitor those !4 cm One to three follow-upCTs (median 3,average 2.3)

Table 8 Implications of current clinical recommendations, applying the data described in the current paper.

Approximate risk of event during 2-year radiological follow-up and 4-year biochemical follow-up of an adrenal incidentalomainitially thought to be benign and non-functional

Approximate financial cost of tests 1630 US$ (based on average 2.3 scans)Radiation exposure from CT imaging during follow-up 23 mSvRisk of inducing fatal cancer from radiation exposure during follow-up CT imaging 1 in 430 to 1 in 2170a

Risk of detecting cancer during follow-up 0–1 in 500b

Risk of detecting non-metastatic cancer during follow-up 0–1 in 1000Risk of false-positive diagnosis/suspicion of malignancy during CT imaging 1 in 20c

Risk of false-positive diagnosis of subclinical Cushing’s syndrome Between 1 in 10 and 1 in 4d

Risk of true-positive diagnosis of subclinical Cushing’s syndrome 1 in 250e

aBased on risk of causing fatal cancer of between 1 in 1000 and 1 in 5000 CT scans, and 2.3 CT scans occurring during follow-up.bApproximately, half of tumours detected will be metastases, and so diagnosis unlikely to affect outcome.cBased on specificity of CT of 95% for malignancy, see Table 6.dBased on specificity of 1 mg DXT of 90% and four annual follow-up tests.eBased on 2 cases per 1000 developing over 2 years of follow-up, see Table 6.

Evaluation of adrenal incidentalomas 523EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161

only offering a small chance of a true-positivediagnosis (often of debatable clinical benefit, such assubclinical Cushing’s syndrome or an adrenal metas-tasis). At initial evaluation, the false-positive rate forfunctional or malignant lesions is typically 5 timesgreater than the true-positive rate, and during follow-up of adrenal incidentalomas initially considered to bebenign and non-functional, the false-positive rate istypically 50 times greater than the true-positive rate(Tables 5 and 6).

The cost to the patient of repeated clinic visits bothfinancially, and also in terms of inconvenience andpsychological distress, is impossible to quantify but islikely to be significant. The financial costs to the health-care system are approximately US$ 1630 for the testsalone (based on performing 2.3 CT scans, plus annualroutine biochemistry, cortisol as part of 1 mg DXT,urinary catecholamines and metanephrines, renin andaldosterone for 4 years), without allowing for additionalcosts such as hospital overheads, consultation time andfurther evaluation of positive results. There should alsobe consideration of the costs associated with unnecess-ary adrenalectomy.

The CT imaging recommended exposes the averagepatient to 23 mSv of ionising radiation, and so exposesthe individual to a chance of inducing fatal cancer ofbetween 1 in 430 and 1 in 2170 (based on a risk of deathof between 1 in 1000 and 1 in 5000, per singleabdominal CT scan of 10 mSv). This is comparablewith the risk of detecting an adrenal malignancy during3 year follow-up of between 0 and 1 in 500 (based onmedian incidence of 0%, mean incidence 0.2%; Table 3).

It is important to comment in more detail on the twocancers detected during follow-up in the papers includedin this review. The first was a renal carcinoma metastasisin a patient with a known history of renal carcinoma(19), and since patients with known malignancy are atincreased risk of developing adrenal metastases, onecould reasonably argue that this study should have beenexcluded from this analysis. Moreover, there is no provenbenefit of adrenalectomy in patients found to have

adrenal metastases during the investigation of adrenalincidentalomas (1). The other malignancy detectedduring follow-up showed a mass enlargement after 6months and the patient was eventually diagnosed withnon-Hodgkin’s lymphoma (45).

Current practice of interval CT imaging, consistingof two to three follow-up scans, is therefore almostas likely to cause fatal cancer as it is to find cancer(half of which are likely to already be disseminated), andso on a policy level is difficult to justify. In addition,because of the low prevalence of malignancy orendocrine functionality developing during follow-up ofan adrenal incidentaloma initially thought to be benignand non-functional, the performance of the availablediagnostic tests is poor, with many more false positivesthan true positives (Table 8).

Conclusion

The precise figures presented are clearly open tocriticism, partly due to the heterogeneity of the studiesthat have, and have not, been included in this review.However, such debate would distract from the broadconclusions that can reasonably be drawn from the datain the literature, which can be summarised as follows:

– The prevalence of endocrine functionality in adrenalincidentalomas is low (!10%).

– The prevalence of malignancy in adrenal incidenta-lomas is lower (!5%).

– The majority of cases of endocrine functionality aredue to subclinical Cushing’s syndrome, the clinicalimportance of which is debatable.

– The risk of an adrenal incidentaloma, initiallythought to be benign and non-functional, sub-sequently developing clinically important endocrinefunctionality or malignancy over 2–4 years is low, inthe region of !1%, but does vary depending uponthe definition of, and extent of testing for, subclinicalCushing’s syndrome.

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524 T J Cawood and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161

– Due to the low prevalence of these conditions,especially during follow-up, and the less-than-idealperformance of the tests used to diagnose endocrinefunctionality and malignancy, the chances of false-positive tests are many times higher than the chanceof a true-positive result.

– The chance of detecting malignancy during CTfollow-up of adrenal incidentalomas initially thoughtto be benign and non-functional is broadly similar tothe chance of inducing fatal cancer from the ionisingradiation delivered by these CT scans.

In the light of these data, current practice is arguablydifficult to defend on a number of levels including thestandards of Hippocrates ‘Primum non nocere’ (first do noharm). Acceptable results, but with considerably lessexpense, both financial and emotional due to false-positive test results, could be obtained by takingreasonable steps to exclude functionality and malig-nancy at presentation (such as those recommended bythe NIH Consensus statement and leading reviewssummarised in Table 7 (1–3)), but not embarking oneither biochemical or imaging follow-up in thosethought to be benign and non-functioning. For thosein a ‘grey zone’ – for example 4–6 cm lesions or othersuspicious imaging characteristics, a single imagingfollow-up study 3–6 months later could be undertaken.This follow-up imaging could be with MRI to reduceradiation exposure, although keeping with the sameimaging modality has technical advantages for intervalcomparison. Based on the data presented, the defaultposition after initial evaluation should be to eitherexcise the lesion or discharge from follow-up. The smallnumber of patients who subsequently develop clinicalsigns of hormone excess or malignancy should beinvestigated appropriately.

Further follow-up studies of patients with adrenalincidentalomas are required to define the optimalinvestigation algorithm that balances the false-positiveand negative rates of endocrine test protocols as well asthe financial and emotional costs of investigation. Wewould also argue that the data linking radiationexposure with future cancer risk must also beconsidered when formulating a management algorithm.Based on the available data reviewed in this paper, ourview is that current clinical recommendations for theassessment and management of adrenal incidentalomashave yet to find the optimal balance.

Declaration of interest

The authors declare that there is no conflict of interest that could beperceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any fundingagency in the public, commercial or not-for-profit sector.

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Received 14 April 2009

Accepted 5 May 2009

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